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Open Access 01-12-2013 | Research

Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas

Authors: Emma V Bird, Claire R Christmas, Alison R Loescher, Keith G Smith, Peter P Robinson, Joel A Black, Stephen G Waxman, Fiona M Boissonade

Published in: Molecular Pain | Issue 1/2013

Abstract

Background

Voltage-gated sodium channels Nav1.8 and Nav1.9 are expressed preferentially in small diameter sensory neurons, and are thought to play a role in the generation of ectopic activity in neuronal cell bodies and/or their axons following peripheral nerve injury. The expression of Nav1.8 and Nav1.9 has been quantified in human lingual nerves that have been previously injured inadvertently during lower third molar removal, and any correlation between the expression of these ion channels and the presence or absence of dysaesthesia investigated.

Results

Immunohistochemical processing and quantitative image analysis revealed that Nav1.8 and Nav1.9 were expressed in human lingual nerve neuromas from patients with or without symptoms of dysaesthesia. The level of Nav1.8 expression was significantly higher in patients reporting pain compared with no pain, and a significant positive correlation was observed between levels of Nav1.8 expression and VAS scores for the symptom of tingling. No significant differences were recorded in the level of expression of Nav1.9 between patients with or without pain.

Conclusions

These results demonstrate that Nav1.8 and Nav1.9 are present in human lingual nerve neuromas, with significant correlations between the level of expression of Nav1.8 and symptoms of pain. These data provide further evidence that changes in expression of Nav1.8 are important in the development and/or maintenance of nerve injury-induced pain, and suggest that Nav1.8 may be a potential therapeutic target.

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Nystrom B, Hagbarth KE: Microelectrode recordings from transected nerves in amputees with phantom limb pain. Neurosci Lett 1981, 27: 211–216. 10.1016/0304-3940(81)90270-6CrossRefPubMed

Devor M, Govrin-Lippmann R: Axoplasmic transport block reduces ectopic impulse generation in injured peripheral nerves. Pain 1983, 16: 73–85. 10.1016/0304-3959(83)90087-8CrossRefPubMed

Burchiel KJ: Effects of electrical and mechanical stimulation on two foci of spontaneous activity which develop in primary afferent neurons after peripheral axotomy. Pain 1984, 18: 249–265. 10.1016/0304-3959(84)90820-0CrossRefPubMed

Dib-Hajj SD, Black JA, Waxman SG: Voltage-gated sodium channels: therapeutic targets for pain. Pain Med 2009, 10: 1260–1269. 10.1111/j.1526-4637.2009.00719.xCrossRefPubMed

Dib-Hajj SD, Cummins TR, Black JA, Waxman SG: Sodium channels in normal and pathological pain. Annu Rev Neurosci 2010, 33: 325–347. 10.1146/annurev-neuro-060909-153234CrossRefPubMed

Levinson SR, Luo S, Henry MA: The role of sodium channels in chronic pain. Muscle Nerve 2012, 46: 155–165. 10.1002/mus.23314PubMedCentralCrossRefPubMed

Waxman SG, Cummins TR, Dib-Hajj S, Fjell J, Black JA: Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain. Muscle Nerve 1999, 22: 1177–1187. 10.1002/(SICI)1097-4598(199909)22:9<1177::AID-MUS3>3.0.CO;2-PCrossRefPubMed

Devor M: Sodium channels and mechanisms of neuropathic pain. J Pain 2006, 7: S3-S12.CrossRefPubMed

Cummins TR, Sheets PL, Waxman SG: The roles of sodium channels in nociception: implications for mechanisms of pain. Pain 2007, 131: 243–257. 10.1016/j.pain.2007.07.026PubMedCentralCrossRefPubMed

10.

Mert T: Roles of axonal voltage-dependent ion channels in damaged peripheral nerves. Eur J Pharmacol 2007, 568: 25–30. 10.1016/j.ejphar.2007.05.004CrossRefPubMed

11.

Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG: Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol 2008, 64: 644–653. 10.1002/ana.21527CrossRefPubMed

12.

Djouhri L, Fang X, Okuse K, Wood JN, Berry CM, Lawson SN: The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons. J Physiol 2003, 550: 739–752. 10.1113/jphysiol.2003.042127PubMedCentralCrossRefPubMed

13.

Djouhri L, Newton R, Levinson SR, Berry CM, Carruthers B, Lawson SN: Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav 1.7 (PN1) Na + channel alpha subunit protein. J Physiol 2003, 546: 565–576. 10.1113/jphysiol.2002.026559PubMedCentralCrossRefPubMed

14.

Sangameswaran L, Fish LM, Koch BD, Rabert DK, Delgado SG, Ilnicka M, Jakeman LB, Novakovic S, Wong K, Sze P, et al.: A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia. J Biol Chem 1997, 272: 14805–14809. 10.1074/jbc.272.23.14805CrossRefPubMed

15.

Akopian AN, Sivilotti L, Wood JN: A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 1996, 379: 257–262. 10.1038/379257a0CrossRefPubMed

16.

Dib-Hajj SD, Tyrrell L, Black JA, Waxman SG: NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc Natl Acad Sci U S A 1998, 95: 8963–8968. 10.1073/pnas.95.15.8963PubMedCentralCrossRefPubMed

17.

Tate S, Benn S, Hick C, Trezise D, John V, Mannion RJ, Costigan M, Plumpton C, Grose D, Gladwell Z, et al.: Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons. Nat Neurosci 1998, 1: 653–655. 10.1038/3652CrossRefPubMed

18.

Shields SD, Ahn HS, Yang Y, Han C, Seal RP, Wood JN, Waxman SG, Dib-Hajj SD: Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain 2012, 153: 2017–2030. 10.1016/j.pain.2012.04.022CrossRefPubMed

19.

Dib-Hajj SD, Rush AM, Cummins TR, Hisama FM, Novella S, Tyrrell L, Marshall L, Waxman SG: Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain 2005, 128: 1847–1854. 10.1093/brain/awh514CrossRefPubMed

20.

Dib-Hajj SD, Yang Y, Black JA, Waxman SG: The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci 2013, 14: 49–62.CrossRefPubMed

21.

Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, et al.: Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012, 71: 26–39. 10.1002/ana.22485CrossRefPubMed

22.

Bird EV, Robinson PP, Boissonade FM: Na(v)1.7 sodium channel expression in human lingual nerve neuromas. Arch Oral Biol 2007, 52: 494–502. 10.1016/j.archoralbio.2006.11.011CrossRefPubMed

23.

Loescher AR, Smith KG, Robinson PP: Nerve damage and third molar removal. Dent Update 2003, 30: 375–382.PubMed

24.

Fried K, Bongenhielm U, Boissonade FM, Robinson PP: Nerve injury-induced pain in the trigeminal system. Neuroscientist 2001, 7: 155–165. 10.1177/107385840100700210CrossRefPubMed

25.

Robinson PP, Loescher AR, Yates JM, Smith KG: Current management of damage to the inferior alveolar and lingual nerves as a result of removal of third molars. Br J Oral Maxillofac Surg 2004, 42: 285–292.CrossRefPubMed

26.

Morgan CR, Bird EV, Robinson PP, Boissonade FM: TRPA1 expression in human lingual nerve neuromas in patients with and without symptoms of dysaesthesia. Neurosci Lett 2009, 465: 189–193. 10.1016/j.neulet.2009.08.055CrossRefPubMed

27.

Morgan CR, Bird EV, Robinson PP, Boissonade FM: Immunohistochemical analysis of the purinoceptor P2X7 in human lingual nerve neuromas. J Orofac Pain 2009, 23: 65–72.PubMed

28.

Biggs JE, Yates JM, Loescher AR, Clayton NM, Boissonade FM, Robinson PP: Vanilloid receptor 1 (TRPV1) expression in lingual nerve neuromas from patients with or without symptoms of burning pain. Brain Res 2007, 1127: 59–65.CrossRefPubMed

29.

Biggs JE, Yates JM, Loescher AR, Clayton NM, Robinson PP, Boissonade FM: P2X(3) expression is not altered by lingual nerve injury. Neurosci Lett 2008, 441: 110–114. 10.1016/j.neulet.2008.05.118CrossRefPubMed

30.

England JD, Gamboni F, Ferguson MA, Levinson SR: Sodium channels accumulate at the tips of injured axons. Muscle Nerve 1994, 17: 593–598. 10.1002/mus.880170605CrossRefPubMed

31.

England JD, Happel LT, Kline DG, Gamboni F, Thouron CL, Liu ZP, Levinson SR: Sodium channel accumulation in humans with painful neuromas. Neurology 1996, 47: 272–276. 10.1212/WNL.47.1.272CrossRefPubMed

32.

Coward K, Plumpton C, Facer P, Birch R, Carlstedt T, Tate S, Bountra C, Anand P: Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain 2000, 85: 41–50. 10.1016/S0304-3959(99)00251-1CrossRefPubMed

33.

Kretschmer T, Happel LT, England JD, Nguyen DH, Tiel RL, Beuerman RW, Kline DG: Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry. Acta Neurochir (Wien) 2002, 144: 803–810. 10.1007/s00701-002-0970-1CrossRef

34.

Davies SL, Loescher AR, Clayton NM, Bountra C, Robinson PP, Boissonade FM: Changes in sodium channel expression following trigeminal nerve injury. Exp Neurol 2006, 202: 207–216. 10.1016/j.expneurol.2006.05.035CrossRefPubMed

35.

Cummins TR, Dib-Hajj SD, Black JA, Akopian AN, Wood JN, Waxman SG: A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J Neurosci 1999, 19: RC43.PubMed

36.

Dib-Hajj SD, Ishikawa K, Cummins TR, Waxman SG: Insertion of a SNS-specific tetrapeptide in S3-S4 linker of D4 accelerates recovery from inactivation of skeletal muscle voltage-gated Na channel mu1 in HEK293 cells. FEBS Lett 1997, 416: 11–14. 10.1016/S0014-5793(97)01154-XCrossRefPubMed

37.

Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, et al.: The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 1999, 2: 541–548. 10.1038/9195CrossRefPubMed

38.

Laird JM, Souslova V, Wood JN, Cervero F: Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci 2002, 22: 8352–8356.PubMed

39.

Kerr BJ, Souslova V, McMahon SB, Wood JN: A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain. Neuroreport 2001, 12: 3077–3080. 10.1097/00001756-200110080-00019CrossRefPubMed

40.

Lai J, Gold MS, Kim CS, Bian D, Ossipov MH, Hunter JC, Porreca F: Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 2002, 95: 143–152. 10.1016/S0304-3959(01)00391-8CrossRefPubMed

41.

Cummins TR, Waxman SG: Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci 1997, 17: 3503–3514.PubMed

42.

Rizzo MA, Kocsis JD, Waxman SG: Selective loss of slow and enhancement of fast Na + currents in cutaneous afferent dorsal root ganglion neurones following axotomy. Neurobiol Dis 1995, 2: 87–96. 10.1006/nbdi.1995.0009CrossRefPubMed

43.

Bongenhielm U, Nosrat CA, Nosrat I, Eriksson J, Fjell J, Fried K: Expression of sodium channel SNS/PN3 and ankyrin(G) mRNAs in the trigeminal ganglion after inferior alveolar nerve injury in the rat. Exp Neurol 2000, 164: 384–395. 10.1006/exnr.2000.7437CrossRefPubMed

44.

Ostman JA, Nassar MA, Wood JN, Baker MD: GTP up-regulated persistent Na + current and enhanced nociceptor excitability require NaV1.9. J Physiol 2008, 586: 1077–1087.PubMedCentralCrossRefPubMed

45.

Maingret F, Coste B, Padilla F, Clerc N, Crest M, Korogod SM, Delmas P: Inflammatory mediators increase Nav1.9 current and excitability in nociceptors through a coincident detection mechanism. J Gen Physiol 2008, 131: 211–225. 10.1085/jgp.200709935PubMedCentralCrossRefPubMed

46.

Renton T, Yiangou Y, Tate S, Bountra C, Anand P: Sodium channel Nav1.8 immunoreactivity in painful human dental pulp. BMC Oral Health 2005, 5: 5. 10.1186/1472-6831-5-5PubMedCentralCrossRefPubMed

47.

Suwanchai A, Theerapiboon U, Chattipakorn N, Chattipakorn SC: NaV 1.8, but not NaV 1.9, is upregulated in the inflamed dental pulp tissue of human primary teeth. Int Endod J 2012, 45: 372–378. 10.1111/j.1365-2591.2011.01986.xCrossRefPubMed

48.

Wells JE, Bingham V, Rowland KC, Hatton J: Expression of Nav1.9 channels in human dental pulp and trigeminal ganglion. J Endod 2007, 33: 1172–1176. 10.1016/j.joen.2007.05.023CrossRefPubMed

49.

Strickland IT, Martindale JC, Woodhams PL, Reeve AJ, Chessell IP, McQueen DS: Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur J Pain 2008, 12: 564–572. 10.1016/j.ejpain.2007.09.001CrossRefPubMed

50.

Vora AR, Loescher AR, Craig GT, Boissonade FM, Robinson PP: A light microscopical study on the structure of traumatic neuromas of the human lingual nerve. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005, 99: 395–403. 10.1016/j.tripleo.2004.08.011CrossRefPubMed

51.

Robinson PP, Loescher AR, Smith KG: A prospective, quantitative study on the clinical outcome of lingual nerve repair. Br J Oral Maxillofac Surg 2000, 38: 255–263. 10.1054/bjom.2000.0463CrossRefPubMed

52.

Fjell J, Hjelmstrom P, Hormuzdiar W, Milenkovic M, Aglieco F, Tyrrell L, Dib-Hajj S, Waxman SG, Black JA: Localization of the tetrodotoxin-resistant sodium channel NaN in nociceptors. Neuroreport 2000, 11: 199–202. 10.1097/00001756-200001170-00039CrossRefPubMed

Title: Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas
Authors: Emma V Bird
Claire R Christmas
Alison R Loescher
Keith G Smith
Peter P Robinson
Joel A Black
Stephen G Waxman
Fiona M Boissonade
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2013
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-9-52

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Springer Medicine

Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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